Search

Counselors and educators must re-imagine social-emotional wellness as an essential part of the academic curriculum. The authors present a collaborative, sustainable model that focuses both on academic rigor and emotional wellness. The authors outline how this model can be integrated in any academic content area and how school counselors and teachers can support each other to meet academic and social-emotional learning outcomes. The authors demonstrate how this model can be integrated into high school math.

Abstract Background Australia’s clinical trials sector is highly productive with continued sector investment needed to enhance research impact. Generating economic evidence alongside trials has the potential to facilitate the implementation of trial results into practice. Ascertaining the use of health economic evaluations alongside clinical trials can assist in determining whether clinical trials fully realize and operationalize their potential to change policy and practice. The aims of this study were to ascertain the uptake of health economic evaluations alongside Australian-led clinical trials and explore associations between uptake and trial characteristics. Methods This observational study comprised a descriptive analysis of clinical trials registries, a cross-sectional survey of Australian Clinical Trials Alliance (ACTA) networks, and a subgroup analysis of completed acute care trials. Descriptive analyses of trial registrations were conducted, with logistic regressions used to identify predictors of proposing and subsequently publishing a health economic evaluation alongside acute care trials. Results Few randomized Australian-led clinical trials (11% of 9251) and ACTA network trials (43% of 227) proposed a health economic evaluation. In the subgroup analysis, 22% of the 324 acute care trials and 53% of the 38 ACTA network acute care trials proposed a health economic evaluation. Acute care trials funded by government bodies were significantly more likely to propose and publish a health economic evaluation than those funded by hospitals, universities, and other funders, after adjusting for phase, registration year, primary sponsor type, and comparator. Conclusions Current uptake of health economic evaluations alongside Australian-led clinical trials is low, with uptake higher among the subset of ACTA network trials. This is despite economic evidence playing an increasingly prominent role in health system management, as well as rising health expenditure, limited budgets, and competing demands. There is significant opportunity to embed health economic evaluations alongside clinical trials, particularly phase 3 trials, to increase research outputs and optimize research translation. Investing in clinical trial networks that support funding for a health economist or a health economic evaluation may be an effective strategy to increase the uptake of health economic evaluations alongside trials.

Abstract Osteosarcoma is the most common primary bone malignancy in children and young adults, and it has few treatment options. As a result, there has been little improvement in survival outcomes in the past few decades. The need for models to test novel therapies is especially great in this disease since it is both rare and does not respond to most therapies. To address this, an NCI-funded consortium has characterized and utilized a panel of patient-derived xenograft models of osteosarcoma for drug testing. The exomes, transcriptomes, and copy number landscapes of these models have been presented previously. This study now adds whole genome sequencing and reverse-phase protein array profiling data, which can be correlated with drug testing results. In addition, four additional osteosarcoma models are described for use in the research community.

Abstract Wilms tumor (WT) is the most common renal malignancy of childhood. Despite improvements in the overall survival, relapse occurs in ~15% of patients with favorable histology WT (FHWT). Half of these patients will succumb to their disease. Identifying novel targeted therapies remains challenging in part due to the lack of faithful preclinical in vitro models. Here we establish twelve patient-derived WT cell lines and demonstrate that these models faithfully recapitulate WT biology using genomic and transcriptomic techniques. We then perform loss-of-function screens to identify the nuclear export gene, XPO1, as a vulnerability. We find that the FDA approved XPO1 inhibitor, KPT-330, suppresses TRIP13 expression, which is required for survival. We further identify synergy between KPT-330 and doxorubicin, a chemotherapy used in high-risk FHWT. Taken together, we identify XPO1 inhibition with KPT-330 as a potential therapeutic option to treat FHWTs and in combination with doxorubicin, leads to durable remissions in vivo.

Introduction Patient-reported outcome measures (PROMs) are validated and standardised questionnaires that capture patients’ own reports of their symptoms, functioning and well-being. PROMs can facilitate communication between patients and clinicians, reduce symptom burden, enhance quality of life and inform health service re-design. We aim to determine the acceptability of PROMs and the preferred timing of PROM completion in New South Wales (NSW) at the point of care, facilitated by the Health Outcomes and Patient Experiences (HOPE) platform.Methods and analysis Semi-structured interviews with patients (~50-75, sampling across seven language groups and seven clinical cohorts), carers (~10–20) and clinicians (~18) enrolled in HOPE will be conducted via videoconference, telephone or in person. Participants will be asked questions about (1) what makes PROMs acceptable for use in chronic disease management (2) when patients would prefer to complete PROMs and when clinicians would like to use PROMs for clinical decision-making and (3) factors that impede the acceptability of PROMs for culturally and linguistically diverse patients. Interviews will be analysed using a reflexive thematic approach, guided by Normalisation Process Theory.Ethics and dissemination Ethics approval has been obtained from the Sydney Local Health District Human Research Ethics Committee (SLHD HREC, Study Protocol #X24-0138). Results will be published in appropriate peer-reviewed journals, presented at conferences, disseminated to participants in the form of a plain language summary, and widely disseminated to consumer groups and professional stakeholders.

Background: Advances in targeted therapy development and tumor sequencing technology are reclassifying cancers into smaller biomarker-defined diseases. Randomized controlled trials (RCTs) are often impractical in rare diseases, leading to calls for single-arm studies to be sufficient to inform clinical practice based on a strong biological rationale. However, without RCTs, favorable outcomes are often attributed to therapy but may be due to a more indolent disease course or other biases. When the clinical benefit of targeted therapy in a common cancer is established in RCTs, this benefit may extend to rarer cancers sharing the same biomarker. However, careful consideration of the appropriateness of extending the existing trial evidence beyond specific cancer types is required. A framework for extrapolating evidence for biomarker-targeted therapies to rare cancers is needed to support transparent decision-making. Objectives: To construct a framework outlining the breadth of criteria essential for extrapolating evidence for a biomarker-targeted therapy generated from RCTs in common cancers to different rare cancers sharing the same biomarker. Design: A series of questions articulating essential criteria for extrapolation. Methods: The framework was developed from the core topics for extrapolation identified from a previous scoping review of methodological guidance. Principles for extrapolation outlined in guidance documents from the European Medicines Agency, the US Food and Drug Administration, and Australia’s Medical Services Advisory Committee were incorporated. Results: We propose a framework for assessing key assumptions of similarity of the disease and treatment outcomes between the common and rare cancer for five essential components: prognosis of the biomarker-defined cancer, biomarker test analytical validity, biomarker actionability, treatment efficacy, and safety. Knowledge gaps identified can be used to prioritize future studies. Conclusion: This framework will allow systematic assessment, standardize regulatory, reimbursement and clinical decision-making, and facilitate transparent discussions between key stakeholders in drug assessment for rare biomarker-defined cancers.

Abstract We propose a quantum processor architecture, the qubit ‘pipeline’, in which run-time scales additively as functions of circuit depth and run repetitions. Run-time control is applied globally, reducing the complexity of control and interconnect resources. This simplification is achieved by shuttling N-qubit states through a large layered physical array of structures which realise quantum logic gates in stages. Thus, the circuit depth corresponds to the number of layers of structures. Subsequent N-qubit states are ‘pipelined’ densely through the structures to efficiently wield the physical resources for repeated runs. Pipelining thus lends itself to noisy intermediate-scale quantum (NISQ) applications, such as variational quantum eigensolvers, which require numerous repetitions of the same or similar calculations. We illustrate the architecture by describing a realisation in the naturally high-density and scalable silicon spin qubit platform, which includes a universal gate set of sufficient fidelity under realistic assumptions of qubit variability.

This review describes the critical factors on which successful grapevine propagation depends and discusses the steps that can be taken to improve the quality of planting material available to growers. Spasmodic occurrences of young vine decline and the failure of planting material have plagued the wine industry since the 1990s. The syndrome now described as Petri disease has been identified as the probable cause of many of the failures, but hot water treatment (HWT) of dormant cuttings (50°C/30 min), for the control of Phaeomoniella chlamydospora and other endogenous pathogens, has also been implicated in the losses. HWT is known to cause a temporary switch to fermentative respiration and early retarded growth in treated material, particularly in Pinot Noir, but the effects of HWT on dormant vine tissue are not yet fully understood. Poor nursery hygiene and poor storage and handling practices during propagation and planting have also been implicated in vine failure. Demand for planting material has exceeded supply and there has been little incentive for nurseries to improve their standards. The quality of planting material could be significantly improved by changing nursery practices, particularly by discontinuing the practice of soaking cuttings in water, treated or untreated, and by improving general standards of nursery hygiene and the management of cool rooms. There is a need to develop a set of universal quality standards for cuttings and rooted vines. Growers also need to be made aware of the characteristics and benefits of high quality planting material.

Abstract Developing synchronous bilateral Wilms tumor suggests an underlying (epi)genetic predisposition. Here, we evaluate this predisposition in 68 patients using whole exome or genome sequencing (n = 85 tumors from 61 patients with matched germline blood DNA), RNA-seq (n = 99 tumors), and DNA methylation analysis (n = 61 peripheral blood, n = 29 non-diseased kidney, n = 99 tumors). We determine the predominant events for bilateral Wilms tumor predisposition: 1)pre-zygotic germline genetic variants readily detectable in blood DNA [WT1 (14.8%), NYNRIN (6.6%), TRIM28 (5%), and BRCA-related genes (5%)] or 2)post-zygotic epigenetic hypermethylation at 11p15.5 H19/ICR1 that may require analysis of multiple tissue types for diagnosis. Of 99 total tumor specimens, 16 (16.1%) have 11p15.5 normal retention of imprinting, 25 (25.2%) have 11p15.5 copy neutral loss of heterozygosity, and 58 (58.6%) have 11p15.5 H19/ICR1 epigenetic hypermethylation (loss of imprinting). Here, we ascertain the epigenetic and genetic modes of bilateral Wilms tumor predisposition.

Abstract Introduction The COVID‐19 pandemic caused rapid implementation of telehealth for melanoma follow‐up care in Australia. This study explores Australian melanoma patients and clinicians' level of satisfaction with telehealth. Methods A cross‐sectional study was conducted across three specialist melanoma centres in Sydney, Australia. Melanoma patients (all stages) and clinicians completed mixed methods surveys seeking socio‐demographic and clinical information and questionnaires to assess satisfaction with telehealth. Additionally, patients completed measures of quality of life, fear of cancer recurrence and trust in their oncologist. Patients and clinicians provided open‐ended responses to qualitative questions about their perceptions of telehealth. Results One hundred and fifteen patients and 13 clinicians responded to surveys. Telephone was used by 109 (95%) patients and 11 (85%) clinicians. Fifty‐seven (50%) patients and nine (69%) clinicians preferred face‐to‐face consultations, 38 (33%) patients and 3 (23%) clinicians preferred a combination of face‐to‐face and telehealth consultations. Five (4%) patients and nil clinicians preferred telehealth consultations. Patients diagnosed with early‐stage melanoma, using telehealth for the first time, who have lower trust in their oncologist, and having higher care delivery, communication and supportive care concerns were likely to report lower satisfaction with telehealth. Open‐ended responses were consistent between patients and clinicians, who reported safety, convenience and improved access to care as major benefits, while identifying personal, interpersonal, clinical and system‐related disadvantages. Discussion While telehealth has been widely implemented during COVID‐19, the benefits identified by patients and clinicians may extend past the pandemic. Telehealth may be considered for use in conjunction with face‐to‐face consultations to provide melanoma follow‐up care.

Abstract Background Patients with kidney failure on hemodialysis (HD) experience considerable symptom burden and poor health-related quality of life (HRQoL). There is limited use of patient reported outcome measures (PROMs) in facility HD units to direct immediate care, with response rates in other studies between 36 to 70%. The aim of this pilot study was to evaluate feasibility of electronic PROMs (e-PROMs) in HD participants, with feedback 3-monthly to the participants’ treating team, for severe or worsening symptoms as identified by the Integrated Palliative Outcome Scale (IPOS-Renal), with linkage to the Australian and New Zealand Dialysis and Transplant (ANZDATA) registry, compared with usual care. Methods This is a registry-based cluster-randomized controlled pilot trial involving all adults receiving HD in 4 satellite units in Australia over a 6-month period. HD units were cluster randomized 1:1 to the control (HRQoL data collection only) or intervention arm (symptom monitoring with feedback to treating team every 3 months). Feasibility was assessed by participant response rate (percentage of eligible HD participants, including new incident participants, who completed the questionnaire at each time point); retention rate (percentage of participants who completed the baseline questionnaire and all subsequent measures); and completion time. HRQoL and symptom burden scores are described. Results There were 226 unique participants who completed the e-PROMs (mean age 62 years, 69% males, 78% White-European, median dialysis vintage 1.62 years). At 6 months, response rate and retention rate for the intervention arm were 54% and 68%, respectively, and 89% and 97% in the control arm. Median time to complete IPOS-Renal was 6.6 min (5.3, 10.1) at 3 months, and when combined with the outcome measure (EQ-5D-5L), the median time was 9.4 min (6.9, 13.6) at 6 months. Conclusions Electronic symptom monitoring among HD participants with feedback to clinicians is feasible. Variations in response and retention rates could be potentially explained by the lengthier questionnaire, and higher frequency of data collection time points for participants in the intervention arm. A definitive national RCT is underway. Trial registration ACTRN12618001976279 (07/12/2018).

Background: Care gaps remain in modern health care despite the availability of robust, evidence-based medications. Although sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated profound benefits in improving both cardiovascular and kidney outcomes in patients, the uptake of these medications remain suboptimal, and the causes have not been systematically explored. Objective: The purpose of this study was to use the Consolidated Framework for Implementation Research (CFIR) to describe the barriers and facilitators faced by clinicians in British Columbia, Canada, when prescribing an SGLT2 inhibitor. To achieve this, we conducted semistructured interviews using the CFIR with practicing family physicians, nephrologists, endocrinologists, and cardiologists in British Columbia. Design: Semistructured interviews. Setting: British Columbia, Canada. Participants: Actively practicing family physicians, nephrologists, endocrinologists, and cardiologists in British Columbia. Methods: Twenty-one clinicians were interviewed using questions derived from the CFIR. The audio recordings were transcribed verbatim, and each transcription was individually analyzed in duplicate using thematic analysis. The analysis focused on identifying barriers and facilitators to using SGLT2 inhibitors in clinical practice and coded using the CFIR constructs. Once the transcriptions were coded, overarching themes were created. Results: Five overarching themes were identified to the barriers and facilitators to using SGLT2 inhibitors: current perceptions and beliefs, clinician factors, patient factors, medication factors, and health care system factors. The current perceptions and beliefs were that SGLT2 inhibitors are efficacious and have distinct advantages over other agents but are underutilized in British Columbia. Clinician factors included varying levels of knowledge of and comfort in prescribing SGLT2 inhibitors, and patient factors included intolerable adverse events and additional pill burden, but many were enthusiastic about potential benefits. Multiple SGLT2 inhibitor related adverse events like mycotic infections and euglycemic diabetic ketoacidosis and the difficulty in obtaining reimbursement for these medications were also identified as a barrier to prescribing these medications. Facilitators for the use of SGLT2 inhibitors included consensus among colleagues, influential leaders, and peers in support of their use, and endorsement by national guidelines. Limitations: The experience from the clinicians regarding costs and the reimbursement process is limited to British Columbia as each province has its own procedures. There may be responder bias as clinicians were approached through purposive sampling. Conclusion: This study highlights different themes to the barriers and facilitators of using SGLT2 inhibitors in British Columbia. The identification of these barriers provides a specific target for improvement, and the facilitators can be leveraged for the increased use of SGLT2 inhibitors. Efforts to address and optimize these barriers and facilitators in a systematic approach may lead to an increase in the use of these efficacious medications.

Abstract Layered van der Waals (vdW) magnets can maintain a magnetic order even down to the single-layer regime and hold promise for integrated spintronic devices. While the magnetic ground state of vdW magnets was extensively studied, key parameters of spin dynamics, like the Gilbert damping, crucial for designing ultra-fast spintronic devices, remains largely unexplored. Despite recent studies by optical excitation and detection, achieving spin wave control with microwaves is highly desirable, as modern integrated information technologies predominantly are operated with these. The intrinsically small numbers of spins, however, poses a major challenge to this. Here, we present a hybrid approach to detect spin dynamics mediated by photon-magnon coupling between high-Q superconducting resonators and ultra-thin flakes of Cr2Ge2Te6 (CGT) as thin as 11 nm. We test and benchmark our technique with 23 individual CGT flakes and extract an upper limit for the Gilbert damping parameter. These results are crucial in designing on-chip integrated circuits using vdW magnets and offer prospects for probing spin dynamics of monolayer vdW magnets.

Abstract Introduction Melanoma surveillance photography (MSP) is a comprehensive surveillance method that comprises two- or three-dimensional total body photography with tagged digital dermoscopy, performed at prescribed intervals. It has the potential to reduce unnecessary biopsies and enhance early detection of melanoma, but it is not yet standard care for all high-risk patients in Australia. This protocol describes a randomised controlled trial (RCT) designed to evaluate the clinical impact and cost-effectiveness of using MSP for the surveillance of individuals at ultra-high or high risk of melanoma from a health system perspective. Methods and design This is a registry-based, unblinded, multi-site, parallel-arm RCT that will be conducted over 3 years. We aim to recruit 580 participants from three Australian states: Victoria, New South Wales and Queensland, via state cancer registries or direct referral from clinicians. Eligible participants within 24 months of a primary cutaneous melanoma diagnosis will be randomised 1:1 to receive either MSP in addition to their routine clinical surveillance (intervention group) or routine clinical surveillance without MSP (control group). Most participants will continue surveillance with their usual care provider, and the frequency of follow-up visits in both groups will depend on the stage of their primary melanoma and risk factors. The primary outcome measure of the study is the number of unnecessary biopsies (i.e. false positives, being cases where a lesion is biopsied due to suspected melanoma on clinical examination, either with or without MSP, but the resulting histopathology finding is negative for melanoma). Secondary outcomes include the evaluation of health economic outcomes, quality of life and patient acceptability. Two sub-studies will explore the benefit of MSP in high-risk patients prior to a melanoma diagnosis and the diagnostic performance of MSP in the teledermatology setting compared to the en face clinical setting. Discussion This trial will determine the clinical efficacy, cost-effectiveness and affordability of MSP to facilitate policy decision-making at the national and local levels, across primary and specialist care. Trial registration ClinicalTrials.gov NCT04385732 . Registered on May 13, 2020.

Abstract Background Prioritisation of clinical trials ensures that the research conducted meets the needs of stakeholders, makes the best use of resources and avoids duplication. The aim of this review was to identify and critically appraise approaches to research prioritisation applicable to clinical trials, to inform best practice guidelines for clinical trial networks and funders. Methods A scoping review of English-language published literature and research organisation websites (January 2000 to January 2020) was undertaken to identify primary studies, approaches and criteria for research prioritisation. Data were extracted and tabulated, and a narrative synthesis was employed. Results Seventy-eight primary studies and 18 websites were included. The majority of research prioritisation occurred in oncology and neurology disciplines. The main reasons for prioritisation were to address a knowledge gap (51 of 78 studies [65%]) and to define patient-important topics (28 studies, [35%]). In addition, research organisations prioritised in order to support their institution’s mission, invest strategically, and identify best return on investment. Fifty-seven of 78 (73%) studies used interpretative prioritisation approaches (including Delphi surveys, James Lind Alliance and consensus workshops); six studies used quantitative approaches (8%) such as prospective payback or value of information (VOI) analyses; and 14 studies used blended approaches (18%) such as nominal group technique and Child Health Nutritional Research Initiative. Main criteria for prioritisation included relevance, appropriateness, significance, feasibility and cost-effectiveness. Conclusion Current research prioritisation approaches for groups conducting and funding clinical trials are largely interpretative. There is an opportunity to improve the transparency of prioritisation through the inclusion of quantitative approaches.

Abstract Background Empirical evidence suggests data and insights from the clinical practice guidelines and clinical quality registries are not being fully utilised, leaving health service managers, clinicians and providers without clear guidance on how best to improve healthcare delivery. This lack of uptake of existing research knowledge represents low value to the healthcare system and needs to change. Methods Five electronic databases (MEDLINE, Embase, CINAHL, Cochrane Central and Cochrane Database of Systematic Reviews) were systematically searched. Included studies were published between 2000 and 2020 reporting on the attributes, evidence usage and impact of clinical practice guidelines and clinical quality registries on health service delivery. Results Twenty-six articles including one randomised controlled trial, eight before-and-after studies, eight case studies/reviews, five surveys and four interview studies, covering a wide range of medical conditions and conducted in the USA, Australia and Europe, were identified. Five complementary strategies were derived to maximise the likelihood of best practice health service delivery: (1) feedback and transparency, (2) intervention sustainability, (3) clinical practice guideline adherence, (4) productive partnerships and (5) whole-of-team approach. Conclusion These five strategies, used in context-relevant combinations, are most likely to support the application of existing high-quality data, adding value to health service delivery. The review highlighted the limitations of study design in opportunistic registry studies that do not produce clear, usable evidence to guide changes to health service implementation practices. Recommendations include exploration of innovative methodologies, improved coordination of national registries and the use of incentives to encourage guideline adherence and wider dissemination of strategies used by successful registries.

Purpose: Brain metastases are common in patients with advanced melanoma. This study describes 12-month quality of life (QoL) trajectories following local management of 1–3 melanoma brain metastases. Methods: This study assessed QoL data collected during a multi-center, prospective, open-label, phase III randomized controlled trial comparing the efficacy of adjuvant whole brain radiotherapy (WBRT) with observation after local treatment of 1–3 melanoma brain metastases. Patients completed the European Organization for Research and Treatment of Cancer Quality of Life Core (QLQ-C30) and Brain Tumour (BN-20) questionnaires at baseline and every 2 months, for 12 months.Using growth mixture modelling, QoL trajectories were identified for global health status, QLQ-C30 and BN-20 subscales for patients with baseline and at least one follow-up assessment. Multivariable logistic regression was used to examine associations between trajectories, demographic, and clinical factors. Results: After combining QoL data from observation and WBRT arms, QLQ-C30 and BN-20 trajectories were calculated for 139 and 137 patients respectively. Depending on the QoL domain, 9–54 % of patients reported a deterioration in QoL. Older age (≥65 years) was significantly associated with deterioration in global health status (OR = 2.88, 95 %CI = 1.27–6.54), physical (OR = 3.49, 95 %CI = 1.29–9.41), role (OR = 4.15, 95 %CI = 1.77–9.71), social (OR = 4.42, 95 % CI = 1.57–12.46), cognitive (OR = 6.70, 95 % CI = 1.93–23.29) and motor functioning (OR = 4.95, 95 %CI = 1.95–12.61) and increased future uncertainty (OR = 0.20, 95 %CI = 0.07–0.53). Female sex (OR = 0.10, 95 %CI = 0.02–0.41), not having neurosurgery at baseline (OR = 0.09, 95 %CI = 0.02–0.52), 2–3 brain metastases (OR = 5.75, 95 %CI = 1.76–18.85) or receiving adjuvant WBRT (OR = 6.77, 95 %CI = 2.00–22.99) were associated with poorer physical, emotional, cognitive and social outcomes respectively. Conclusions: Poorer QoL outcomes in the first 12 months after diagnosis of melanoma brain metastases were observed in patients aged ≥ 65 years, females, having 2–3 brain metastases, non-surgical treatment of metastases or adjuvant WBRT.Clinical Trial Registration Number:Whole Brain Radiotherapy Trial (WBRTMel) was registered with the Australian Clinical Trials Registry (ACTRN12607000512426) and ClinicalTrials.gov (NCT01503827).Study Support:This project was funded by Cancer Australia PdCCRS (Grants No. 512358, 1009485, and 1084046) and the National Helath and Medical Research Coucil of Australia (NHMRC; Grant No. 1135285).ADT was supported by a Cancer Australia Priority-driven Collaborative Cancer Research Scheme. Project #1046923. RLM was supported by an NHMRC Fellowship #1194703 and a University of Sydney, Robinson Fellowship. JFT was supported by an NHMRC Program Grant #1093017.

Background. Kidneys from potential deceased donors with brain cancer are often foregone due to concerns of cancer transmission risk to recipients. There may be uncertainty around donors’ medical history and their absolute transmission risk or risk-averse decision-making among clinicians. However, brain cancer transmissions are rare, and prolonging waiting time for recipients is harmful. Methods. We assessed the cost-effectiveness of increasing utilization of potential deceased donors with brain cancer using a Markov model simulation of 1500 patients waitlisted for a kidney transplant, based on linked transplant registry data and with a payer perspective (Australian government). We estimated costs and quality-adjusted life-years (QALYs) for three interventions: decision support for clinicians in assessing donor risk, improved cancer classification accuracy with real-time data-linkage to hospital records and cancer registries, and increased risk tolerance to allow intermediate-risk donors (up to 6.4% potential transmission risk). Results. Compared with current practice, decision support provided 0.3% more donors with an average transmission risk of 2%. Real-time data-linkage provided 0.6% more donors (1.1% average transmission risk) and increasing risk tolerance (accepting intermediate-risk 6.4%) provided 2.1% more donors (4.9% average transmission risk). Interventions were dominant (improved QALYs and saved costs) in 78%, 80%, and 87% of simulations, respectively. The largest benefit was from increasing risk tolerance (mean +18.6 QALYs and AU$2.2 million [US$1.6 million] cost-savings). Conclusions. Despite the additional risk of cancer transmission, accepting intermediate-risk donors with brain cancer is likely to increase the number of donor kidneys available for transplant, improve patient outcomes, and reduce overall healthcare expenditure.

Introduction Type 2 diabetes mellitus (T2DM) is a powerful risk factor for cardiovascular disease (CVD), conferring a greater relative risk in women than men. We sought to examine sex differences in cardiometabolic risk factors and management in the contemporary cohort represented by the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE).Research design and methods GRADE enrolled 5047 participants (1837 women, 3210 men) with T2DM on metformin monotherapy at baseline. The current report is a cross-sectional analysis of baseline data collected July 2013 to August 2017.Results Compared with men, women had a higher mean body mass index (BMI), greater prevalence of severe obesity (BMI≥40 kg/m2), higher mean LDL cholesterol, greater prevalence of low HDL cholesterol, and were less likely to receive statin treatment and achieve target LDL, with a generally greater prevalence of these risk factors in younger women. Women with hypertension were equally likely to achieve blood pressure targets as men; however, women were less likely to receive ACE inhibitors or angiotensin receptor blockers. Women were more likely to be divorced, separated or widowed, and had fewer years of education and lower incomes.Conclusions This contemporary cohort demonstrates that women with T2DM continue to have a greater burden of cardiometabolic and socioeconomic risk factors than men, particularly younger women. Attention to these persisting disparities is needed to reduce the burden of CVD in women.Trial registration number ClinicalTrials.gov (NCT01794143)

Abstract A therapeutic agent that targets both viral replication and the hyper‐reactive immune response would offer a highly desirable treatment for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2; COVID‐19) management. Emvododstat (PTC299) was found to be a potent inhibitor of immunomodulatory and inflammation‐related processes by the inhibition of dihydroorotate dehydrogenase (DHODH) to reduce SARS‐CoV‐2 replication. DHODH is the rate‐limiting enzyme of the de novo pyrimidine nucleotide biosynthesis pathway. This drug interaction study was performed to determine whether emvododstat was an inhibitor of breast cancer resistance protein (BCRP) transporters in humans. Potential drug–drug interactions (DDIs) between emvododstat and a BCRP transporter substrate (rosuvastatin) were investigated by measuring plasma rosuvastatin concentrations before and after emvododstat administration. There was no apparent difference in rosuvastatin plasma exposure. The geometric means of maximum plasma rosuvastatin concentrations (Cmax) were 4369 (rosuvastatin) and 5141 pg/mL (rosuvastatin + emvododstat) at 4 h postdose. Geometric mean rosuvastatin area under the concentration–time curve (AUC) from time 0 to the last measurable plasma concentration was 45 616 and 48 975 h·pg/mL when administered alone and after 7 days of b.i.d. emvododstat dosing, respectively. Geometric least squares mean ratios for Cmax and AUC were approximately equal to 1. Overall, administration of multiple doses of 100 mg emvododstat b.i.d. for 7 days in combination with a single dose of rosuvastatin was safe and well tolerated. Emvododstat can be safely administered with other BCRP substrate drugs. Hence, pharmacokinetic DDI mediated via BCRP inhibition is not expected when emvododstat and BCRP substrates are coadministered.

Background: The prevalence of neonatal abstinence syndrome is increasing, but the number and quality of clinical practice guidelines available are unknown. This systematic review aimed to identify, appraise and evaluate clinical practice guidelines for neonatal abstinence syndrome. Methods: A systematic search of databases and the grey literature was conducted between 1 June and 1 July 2022. Full-text guidelines published by national or state-wide institutions were included. The recommendations from each guideline were extracted. The AGREE-II instrument was used to assess guideline quality. Sufficient-quality scores were defined as >60 and good-quality scores were >80 for each domain of AGREE-II. Results: A total of 1703 records were identified, and 22 guidelines from the United States, Australia, Canada and the United Kingdom, published between 2012 to 2021, were included. The quality scores were low, with median scores of 37/100 for stakeholder involvement, 33/100 for methodology, 34/100 for applicability and 0 for editorial independence. Scope and purpose scored 72/100, and presentation scored 85/100. Sixteen (73%) guidelines did not meet the cut-offs for clinical use. Conclusion: Many guidelines were of insufficient quality to guide clinical practice for neonatal abstinence syndrome. This emphasises the need for high-quality studies to inform clinical practice guidelines, improve care and reduce the risk of poor outcomes in these high-risk infants.

Recombinant adeno-associated virus (rAAV) vectors are increasingly being used for clinical gene transfer and have shown great potential for the treatment of several monogenic disorders. However, contaminant DNA from producer plasmids can be packaged into rAAV alongside the intended expression cassette-containing vector genome. The consequences of this are unknown. Our analysis of rAAV preps revealed abundant contaminant sequences upstream of the AAV replication (Rep) protein driving promoter, P5, on the Rep-Cap producer plasmid. Characterization of P5-associated contaminants after infection showed transfer, persistence, and transcriptional activity in AAV-transduced murine hepatocytes, in addition to in vitro evidence suggestive of integration. These contaminants can also be efficiently translated and immunogenic, revealing previously unrecognized side effects of rAAV-mediated gene transfer. P5-associated contaminant packaging and activity were independent of an inverted terminal repeat (ITR)-flanked vector genome. To prevent incorporation of these potentially harmful sequences, we constructed a modified P5-promoter (P5-HS), inserting a DNA spacer between an Rep binding site and an Rep nicking site in P5. This prevented upstream DNA contamination regardless of transgene or AAV serotype, while maintaining vector yield. Thus, we have constructed an rAAV production plasmid that improves vector purity and can be implemented across clinical rAAV applications. These findings represent new vector safety and production considerations for rAAV gene therapy.

Introduction Cerebral palsy (CP) is the most common physical disability of childhood worldwide. Historically the diagnosis was made between 12 and 24 months, meaning data about effective early interventions to improve motor outcomes are scant. In high-income countries, two in three children will walk. This evaluator-blinded randomised controlled trial will investigate the efficacy of an early and sustained Goals–Activity–Motor Enrichment approach to improve motor and cognitive skills in infants with suspected or confirmed CP.Methods and analysis Participants will be recruited from neonatal intensive care units and the community in Australia across four states. To be eligible for inclusion infants will be aged 3–6.5 months corrected for prematurity and have a diagnosis of CP or ‘high risk of CP’ according to the International Clinical Practice Guideline criteria. Eligible participants whose caregivers consent will be randomly allocated to receive usual care or weekly sessions at home from a GAME-trained study physiotherapist or occupational therapist, paired with a daily home programme, until age 2. The study requires 150 participants per group to detect a 0.5 SD difference in motor skills at 2 years of age, measured by the Peabody Developmental Motor Scales-2. Secondary outcomes include gross motor function, cognition, functional independence, social–emotional development and quality of life. A within-trial economic evaluation is also planned.Ethics and dissemination Ethical approval was obtained from the Sydney Children’s Hospital Network Human Ethics Committee in April 2017 (ref number HREC/17/SCHN/37). Outcomes will be disseminated through peer-reviewed journal publications, presentations at international conferences and consumer websites.Trial registration number ACTRN12617000006347.

We determined weights for a multi-criteria tool for assessing the relative merits of clinical-trial research proposals, and investigated whether the weights vary across relevant stakeholder groups. A cross-sectional, adaptive discrete choice experiment using 1000minds online software was administered to consumers, researchers and funders affiliated with the Australian Clinical Trials Alliance (ACTA). We identified weights for four criteria-Appropriateness, Significance, Relevance, Feasibility-and their levels, representing their relative importance, so that research proposals can be scored between 0% (nil or very low merit) and 100% (very high merit). From 220 complete survey responses, the most important criterion was Appropriateness (adjusted for differences between stakeholder groups, mean weight 28.9%) and the least important was Feasibility (adjusted mean weight 19.5%). Consumers tended to weight Relevance more highly (2.7% points difference) and Feasibility less highly (3.1% points difference) than researchers. The research or grant writing experience of researchers or consumers was not associated with the weights. A multi-criteria tool for evaluating research proposals that reflects stakeholders' preferences was created. The tool can be used to assess the relative merits of clinical trial research proposals and rank them, to help identify the best proposals for funding.

BackgroundThe growing number of melanoma patients who need long-term surveillance increasingly exceeds the capacity of the dermatology workforce, particularly outside of metropolitan areas. Digital technologies that enable patients to perform skin self-examination and send dermoscopic images of lesions of concern to a dermatologist (mobile teledermoscopy) are a potential solution. If these technologies and the remote delivery of melanoma surveillance are to be incorporated into routine clinical practice, they need to be accepted by clinicians providing melanoma care, such as dermatologists and general practitioners (GPs). ObjectiveThis study aimed to explore perceptions of potential benefits and harms of mobile teledermoscopy, as well as experiences with this technology, among clinicians participating in a pilot randomized controlled trial (RCT) of patient-led melanoma surveillance. MethodsThis qualitative study was nested within a pilot RCT conducted at dermatologist and skin specialist GP–led melanoma clinics in New South Wales, Australia. We conducted semistructured interviews with 8 of the total 11 clinicians who were involved in the trial, including 4 dermatologists (3 provided teledermatology, 2 were treating clinicians), 1 surgical oncologist, and 3 GPs with qualifications in skin cancer screening (the remaining 3 GPs declined an interview). Thematic analysis was used to analyze the data with reference to the concepts of “medical overuse” and “high-value care.” ResultsClinicians identified several potential benefits, including increased access to dermatology services, earlier detection of melanomas, reassurance for patients between scheduled visits, and a reduction in unnecessary clinic visits. However, they also identified some potential concerns regarding the use of the technology and remote monitoring that could result in diagnostic uncertainty. These included poor image quality, difficulty making assessments from a 2D digital image (even if good quality), insufficient clinical history provided, and concern that suspicious lesions may have been missed by the patient. Clinicians thought that uncertainty arising from these concerns, together with perceived potential medicolegal consequences from missing a diagnosis, might lead to increases in unnecessary clinic visits and procedures. Strategies suggested for achieving high-value care included managing clinical uncertainty to decrease the potential for medical overuse and ensuring optimal placement of patient-led teledermoscopy within existing clinical care pathways to increase the potential for benefits. ConclusionsClinicians were enthusiastic about the potential and experienced benefits of mobile teledermoscopy; however, managing clinical uncertainty will be necessary to achieve these benefits in clinical care outside of trial contexts and minimize potential harms from medical overuse. Trial RegistrationAustralian and New Zealand Clinical Trials Registry ACTRN12616001716459; https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=371865

Abstract Background Adjuvant immunotherapy is revolutionising care for patients with resected stage III and IV melanoma. However, immunotherapy may be associated with toxicity, making treatment decisions complicated. This study aimed to identify factors physicians and nurses considered regarding adjuvant immunotherapy for melanoma. Methods In-depth interviews were conducted with physicians (medical oncologists, surgeons and dermatologists) and nurses managing patients with resected stage III melanoma at three Australian tertiary melanoma centres between July 2019 and March 2020. Factors considered regarding adjuvant immunotherapy were explored. Recruitment continued until data saturation and thematic analysis was undertaken. Results Twenty-five physicians and nurses, aged 28–68 years, 60% females, including eleven (44%) medical oncologists, eight (32%) surgeons, five (20%) nurses, and one (4%) dermatologist were interviewed. Over half the sample managed five or more new resected stage III patients per month who could be eligible for adjuvant immunotherapy. Three themes about adjuvant immunotherapy recommendations emerged: [1] clinical and patient factors, [2] treatment information provision, and [3] individual physician/nurse factors. Melanoma sub-stage and an individual patient’s therapy risk/benefit profile were primary considerations. Secondary factors included uncertainty about adjuvant immunotherapy’s effectiveness and their views about treatment burden patients might consider acceptable. Conclusions Patients’ disease sub-stage and their treatment risk versus benefit drove the melanoma health care professionals’ adjuvant immunotherapy endorsement. Findings clarify clinician preferences and values, aiding clinical communication with patients and facilitating clinical decision-making about management options for resected stage III melanoma.

Abstract Background Optimising the care of individuals with cancer without imposing significant financial burden related to their anticancer treatment is becoming increasingly difficult. The American Society of Clinical Oncology (ASCO) has recommended clinicians discuss costs of cancer care with patients to enhance shared decision-making. We sought information to guide oncologists’ discussions with patients about these costs. Methods We searched Medline, EMBASE and clinical practice guideline databases from January 2009 to 1 June 2019 for recommendations about discussing the costs of care and financial burden. Guideline quality was assessed with the AGREE-II instrument. Results Twenty-seven guidelines met our eligibility criteria, including 16 from ASCO (59%). 21 of 27 (78%) guidelines included recommendations about discussion or consideration of treatment costs when prescribing, with information about actual costs in four (15%). Recognition of the risk of financial burden or financial toxicity was described in 81% (22/27) of guidelines. However, only nine guidelines (33%) included information about managing the financial burden. Conclusions Current clinical practice guidelines have little information to guide physician-patient discussions about costs of anticancer treatment and management of financial burden. This limits patients’ ability to control costs of treatment, and for the healthcare team to reduce the incidence and severity of financial burden. Current guidelines recommend clinician awareness of price variability and high costs of treatment. Clinicians are recommended to explore cost concerns and address financial worries, especially in high risk groups. Future guidelines should include advice on facilitating cost transparency discussions, with provision of cost information and resources.

Abstract Background Reviews of qualitative studies allow for deeper understanding of concepts and findings beyond the single qualitative studies. Concerns on study reporting quality led to the publication of the COREQ-guidelines for qualitative studies in 2007, followed by the ENTREQ-guidelines for qualitative reviews in 2012. The aim of this meta-review is to: 1) investigate the uptake of the COREQ- and ENTREQ- checklists in qualitative reviews; and 2) compare the quality of reporting of the primary qualitative studies included within these reviews prior- and post COREQ-publication. Methods Reviews were searched on 02-Sept-2020 and categorized as (1) COREQ- or (2) ENTREQ-using, (3) using both, or (4) non-COREQ/ENTREQ. Proportions of usage were calculated over time. COREQ-scores of the primary studies included in these reviews were compared prior- and post COREQ-publication using T-test with Bonferroni correction. Results 1.695 qualitative reviews were included (222 COREQ, 369 ENTREQ, 62 both COREQ/ENTREQ and 1.042 non-COREQ/ENTREQ), spanning 12 years (2007–2019) demonstrating an exponential publication rate. The uptake of the ENTREQ in reviews is higher than the COREQ (respectively 28% and 17%), and increases over time. COREQ-scores could be extracted from 139 reviews (including 2.775 appraisals). Reporting quality improved following the COREQ-publication with 13 of the 32 signalling questions showing improvement; the average total score increased from 15.15 to 17.74 (p-value

Abstract Rationale & Objective Explore priorities related to outcomes and barriers of adults with chronic kidney disease (CKD) regarding person centred care and care planning. Study design Systematic review of qualitative studies. Search Strategy & Sources In July 2018 six bibliographic databases, and reference lists of included articles were searched for qualitative studies that included adults with CKD stages 1–5, not on dialysis or conservative management, without a previous kidney transplantation. Analytical Approach Three independent reviewers extracted and inductively coded data using thematic synthesis. Reporting quality was assessed using the COREQ and the review reported according to PRISMA and ENTREQ statements. Results Forty-six studies involving 1493 participants were eligible. The period after diagnosis of CKD is characterized by feelings of uncertainty, social isolation, financial burden, resentment and fear of the unknown. Patients show interest in ways to return to normality and remain in control of their health in order to avoid further deterioration of kidney function. However, necessary information is often unavailable or incomprehensible. Although patients and healthcare professionals share the predominant interest of whether or not dialysis or transplantation is necessary, patients value many more outcomes that are often unrecognized by their healthcare professionals. We identified 4 themes with 6 subthemes that summarize these findings: ‘pursuing normality and control’ (‘pursuing normality’; ‘a search for knowledge’); ‘prioritizing outcomes’ (‘reaching kidney failure’; ‘experienced health’; ‘social life’; ‘work and economic productivity’); ‘predicting the future’; and ‘realising what matters’. Reporting quality was moderate for most included studies. Limitations Exclusion of non-English articles. Conclusions The realisation that patients’ priorities do not match those of the healthcare professionals, in combination with the prognostic ambiguity, confirms fatalistic perceptions of not being in control when living with CKD. These insights may contribute to greater understanding of patients’ perspectives and a more person-centred approach in healthcare prioritization and care planning within CKD care.

Photosynthetic Complex I (PS-CI) is proposed to couple ferredoxin oxidation and plastoquinone reduction to proton pumping across thylakoid membranes. Here the authors determine the reduction potentials of the iron-sulphur clusters of PS-CI and thus the bioenergetics of the electron transfer relay.

Abstract Background Although many people with chronic low back pain (LBP) improve following conservative treatment, one in five will experience worsening symptoms after discharge from treatment and seek health care again. The current LBP clinical care pathway in many health services lacks a well-integrated, systematic approach to support patients to remain physically active and self-manage their symptoms following discharge from treatment. Health coaching can support people to improve physical activity levels and may potentially reduce health care utilisation for LBP. The primary aim of this study is to evaluate the effect of introducing a coordinated support system (linking hospital outpatient physiotherapy services to a public health coaching service) at discharge from LBP treatment, on the future use of hospital, medical, and health services for LBP, compared with usual care provided at discharge. Methods Three hundred and seventy-four adults with chronic non-specific LBP will be recruited from the outpatient physiotherapy departments of public hospitals in New South Wales, Australia. Participants will be individually randomised to a support system (n = 187) or usual care group (n = 187). All participants will receive usual care provided at discharge from treatment. Participants allocated to the support system will also receive up to 10 telephone-based health coaching sessions, delivered by the Get Healthy Service®, over a 6-month period. Health coaches will monitor and support participants to improve physical activity levels and achieve personal health-related goals. The primary outcome is the total number of encounters with hospital, medical, and health services for LBP, at 12 months from baseline. A within-trial economic evaluation will quantify the incremental costs and benefits of the support system from a health system perspective, to support reimbursement decision making. Discussion This study will establish the effect of a coordinated support system, introduced at discharge from treatment, on the future use of hospital, medical, and health services for LBP and various health outcomes. Conclusion Innovative community-driven solutions to support people with chronic LBP after discharge from treatment are urgently needed. Study findings will help inform health care policy and clinical practice in Australia. Trial Registration Prospectively registered on the Australian New Zealand Clinical Trials Registry ( ACTRN12620000889954 ) on 10/09/2020.

BackgroundCurrent clinician-led melanoma surveillance models require frequent routinely scheduled clinic visits, with associated travel, cost, and time burden for patients. Patient-led surveillance is a new model of follow-up care that could reduce health care use such as clinic visits and medical procedures and their associated costs, increase access to care, and promote early diagnosis of a subsequent new melanoma after treatment of a primary melanoma. Understanding patient experiences may allow improvements in implementation. ObjectiveThis study aims to explore patients’ experiences and perceptions of patient-led surveillance during the 6 months of participation in the MEL-SELF pilot randomized controlled trial. Patient-led surveillance comprised regular skin self-examination, use of a mobile dermatoscope to image lesions of concern, and a smartphone app to track and send images to a teledermatologist for review, in addition to usual care. MethodsSemistructured interviews were conducted with patients previously treated for melanoma localized to the skin in New South Wales, Australia, who were randomized to the patient-led surveillance (intervention group) in the trial. Thematic analysis was used to analyze the data with reference to the technology acceptance model. ResultsWe interviewed 20 patients (n=8, 40% women and n=12, 60% men; median age 62 years). Patients who were more adherent experienced benefits such as increased awareness of their skin and improved skin self-examination practice, early detection of melanomas, and opportunities to be proactive in managing their clinical follow-up. Most participants experienced difficulty in obtaining clear images and technical problems with the app. These barriers were overcome or persevered by participants with previous experience with digital technology and with effective help from a skin check partner (such as a spouse, sibling, or friend). Having too many or too few moles decreased perceived usefulness. ConclusionsPatients with melanoma are receptive to and experience benefits from patient-led surveillance using teledermoscopy. Increased provision of training and technical support to patients and their skin check partners may help to realize the full potential benefits of this new model of melanoma surveillance.

Abstract Background Most subsequent new primary or recurrent melanomas might be self-detected if patients are trained to systematically self-examine their skin and have access to timely medical review (patient-led surveillance). Routinely scheduled clinic visits (clinician-led surveillance) is resource-intensive and has not been shown to improve health outcomes; fewer visits may be possible if patient-led surveillance is shown to be safe and effective. The MEL-SELF trial is a randomised controlled trial comparing patient-led surveillance with clinician-led surveillance in people who have been previously treated for localised melanoma. Methods Stage 0/I/II melanoma patients (n = 600) from dermatology, surgical, or general practice clinics in NSW Australia, will be randomised (1:1) to the intervention (patient-led surveillance, n = 300) or control (usual care, n = 300). Patients in the intervention will undergo a second randomisation 1:1 to polarised (n = 150) or non-polarised (n = 150) dermatoscope. Patient-led surveillance comprises an educational booklet, skin self-examination (SSE) instructional videos; 3-monthly email/SMS reminders to perform SSE; patient-performed dermoscopy with teledermatologist feedback; clinical review of positive teledermoscopy through fast-tracked unscheduled clinic visits; and routinely scheduled clinic visits following each clinician’s usual practice. Clinician-led surveillance comprises an educational booklet and routinely scheduled clinic visits following each clinician’s usual practice. The primary outcome, measured at 12 months, is the proportion of participants diagnosed with a subsequent new primary or recurrent melanoma at an unscheduled clinic visit. Secondary outcomes include time from randomisation to diagnosis (of a subsequent new primary or recurrent melanoma and of a new keratinocyte cancer), clinicopathological characteristics of subsequent new primary or recurrent melanomas (including AJCC stage), psychological outcomes, and healthcare use. A nested qualitative study will include interviews with patients and clinicians, and a costing study we will compare costs from a societal perspective. We will compare the technical performance of two different models of dermatoscope (polarised vs non-polarised). Discussion The findings from this study may inform guidance on evidence-based follow-up care, that maximises early detection of subsequent new primary or recurrent melanoma and patient wellbeing, while minimising costs to patients, health systems, and society. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12621000176864 . Registered on 18 February 2021.

The macroalgae Sargassum has grown for centuries in the oligotrophic North Atlantic supported by natural nutrient sources and cycling. Here the authors show that changes in tissue nutrient contents since the 1980s reflect global anthropogenic nitrogen enrichment, causing blooms in the wider Atlantic basin.

Abstract Background Maintaining employment for adults with cancer is important, however, little is known about the impact of surgery for rectal cancer on an individual's capacity to return to work (RTW). This study aimed to determine the impact of laparoscopic vs. open resection on RTW at 12 months. Methods Analyses were undertaken among participants randomized in the Australian Laparoscopic Cancer of the Rectum Trial (ALaCaRT), with work status available at baseline (presurgery), and 12 months. Multivariable logistic regression, adjusted for sociodemographic and clinical characteristics estimated the effect of surgery on RTW in any capacity, or return to preoperative work status at 12 months. Results About 228 of 449 (51%) surviving trial participants at 12 months completed work status questionnaires; mean age was 62 years, 66% males, 117 of these received laparoscopic resection (51%). Of 228, 120 were employed at baseline (90 full‐time, 30 part‐time). Overall RTW in 120 participants in paid work at baseline was 78% (84% laparoscopic, 70% open surgery). Those employed full‐time were more likely to RTW at 12 months (OR, 3.55; 95% CI, 1.02–12.31). Those with distant metastases at baseline were less likely to RTW (OR, 0.07; 95% CI,

Cobalt (Co) is an important bioactive trace metal that is the metal cofactor in cobalamin (vitamin B12) which can limit or co-limit phytoplankton growth in many regions of the ocean. Total dissolved and labile Co measurements in the Canadian sector of the Arctic Ocean during the U.S. GEOTRACES Arctic expedition (GN01) and the Canadian International Polar Year GEOTRACES expedition (GIPY14) revealed a dynamic biogeochemical cycle for Co in this basin. The major sources of Co in the Arctic were from shelf regions and rivers, with only minimal contributions from other freshwater sources (sea ice, snow) and eolian deposition. The most striking feature was the extremely high concentrations of dissolved Co in the upper 100 m, with concentrations routinely exceeding 800 pmol L−1 over the shelf regions. This plume of high Co persisted throughout the Arctic basin and extended to the North Pole, where sources of Co shifted from primarily shelf-derived to riverine, as freshwater from Arctic rivers was entrained in the Transpolar Drift. Dissolved Co was also strongly organically complexed in the Arctic, ranging from 70 % to 100 % complexed in the surface and deep ocean, respectively. Deep-water concentrations of dissolved Co were remarkably consistent throughout the basin (∼55 pmol L−1), with concentrations reflecting those of deep Atlantic water and deep-ocean scavenging of dissolved Co. A biogeochemical model of Co cycling was used to support the hypothesis that the majority of the high surface Co in the Arctic was emanating from the shelf. The model showed that the high concentrations of Co observed were due to the large shelf area of the Arctic, as well as to dampened scavenging of Co by manganese-oxidizing (Mn-oxidizing) bacteria due to the lower temperatures. The majority of this scavenging appears to have occurred in the upper 200 m, with minimal additional scavenging below this depth. Evidence suggests that both dissolved Co (dCo) and labile Co (LCo) are increasing over time on the Arctic shelf, and these limited temporal results are consistent with other tracers in the Arctic. These elevated surface concentrations of Co likely lead to a net flux of Co out of the Arctic, with implications for downstream biological uptake of Co in the North Atlantic and elevated Co in North Atlantic Deep Water. Understanding the current distributions of Co in the Arctic will be important for constraining changes to Co inputs resulting from regional intensification of freshwater fluxes from ice and permafrost melt in response to ongoing climate change.

Abstract Introduction This study assessed the feasibility and acceptability of FRESH (Families Reporting Every Step to Health), a theory-based child-led family physical activity (PA) intervention delivered online. We also assessed the preliminary effectiveness of the intervention on outcomes of interest and whether pre-specified criteria were met to progress to a full-scale definitive trial. Methods In a three-armed randomised pilot trial, 41 families (with a 7–11-year-old index child) were allocated to a: ‘family’ (FAM), ‘pedometer-only’ (PED), or a no-treatment control (CON) arm. The FAM arm received access to the FRESH website, allowing participants to select step challenges to ‘travel’ to target cities around the world, log their steps, and track progress as families virtually globetrot. FAM and PED arms also received family sets of pedometers. All family members could participate in the evaluation. Physical (e.g., fitness, blood pressure), psychosocial (e.g., social support), behavioural (e.g., objectively-measured PA), and economic (e.g., expenditure for PA) data were collected at baseline, 8- and 52-weeks. Results At 8- and 52-weeks, 98 and 88% of families were retained, respectively. Most children liked participating in the study (> 90%) and thought it was fun (> 80%). Compared to the PED (45%) and CON (39%) arms, a higher percentage of children in the FAM (81%) arm reported doing more activities with their family. Adults agreed that FRESH encouraged their family do more PA and made their family more aware of the amount of PA they do. No notable between-group differences were found for childrens’ minutes in moderate-to-vigorous PA. Sizeable changes of 9.4 (95%CI: 0.4, 18.4) and 15.3 (95%CI: 6.0, 24.5) minutes in moderate-to-vigorous PA was found for adults in the FAM group compared to those in the PED or CON groups, respectively. No other notable differences were found. Conclusion This study demonstrates feasibility and acceptability of the FRESH intervention. All progression criteria were at least partially satisfied. However, we failed to recruit the target sample size and did not find a signal of effectiveness on PA particularly long-term or in children. Further refinements are required to progress to a full-scale trial. Trial registration This study was prospectively registered ( ISRCTN12789422 ) on 16/03/2016.

Abstract Background To measure health-related and care-related quality of life among informal caregivers of older people with end-stage kidney disease (ESKD), and to determine the association between caregiver quality of life and care recipient’s treatment type. Methods A prospective cross-sectional study was conducted. Three renal units in the UK and Australia were included. Informal caregivers of people aged ≥75 years with ESKD managed with dialysis or comprehensive conservative non-dialytic care (estimated glomerular filtration (eGFR) ≤10 mL/min/1.73m2) participated. Health-related quality of life (HRQoL) was assessed using Short-Form six dimensions (SF-6D, 0–1 scale) and care-related quality of life was assessed using the Carer Experience Scale (CES, 0–100 scale). Linear regression assessed associations between care-recipient treatment type, caregiver characteristics and the SF-6D utility index and CES scores. Results Of 63 caregivers, 49 (78%) were from Australia, 26 (41%) cared for an older person managed with dialysis, and 37 (59%) cared for an older person managed with comprehensive conservative care. Overall, 73% were females, and the median age of the entire cohort was 76 years [IQR 68–81]. When adjusted for caregiver sociodemographic characteristics, caregivers reported significantly worse carer experience (CES score 15.73, 95% CI 5.78 to 25.68) for those managing an older person on dialysis compared with conservative care. However, no significant difference observed for carer HRQoL (SF-6D utility index − 0.08, 95% CI − 0.18 to 0.01) for those managing an older person on dialysis compared with conservative care. Conclusions Our data suggest informal caregivers of older people on dialysis have significantly worse care-related quality of life (and therefore greater need for support) than those managed with comprehensive conservative care. It is important to consider the impact on caregivers’ quality of life when considering treatment choices for their care recipients.

Brain tissue is ubiquitous in the archaeological record. Multiple, independent studies report the finding of black, resinous or shiny brain tissue, and Petrone et al. [2020 “Heat-induced Brain Vitrification from the Vesuvius Eruption in C.E. 79.” N Engl J Med. 382: 383–384; doi:10.1056/NEJMc1909867] raise the intriguing prospect of a role for vitrification in the preservation of ancient biomolecules. However, Petrone et al. (2020) have not made their raw data available, and no detailed laboratory or analytical methodology is offered. Issues of contamination and misinterpretation hampered a decade of research in biomolecular archaeology, such that addressing these sources of bias and facilitating validation of specious findings has become both routine and of paramount importance in the discipline. We argue that the evidence they present does not support their conclusion of heat-induced vitrification of human brain tissue, and that future studies should share palaeoproteomic data in an open access repository to facilitate comparative analysis of the recovery of ancient proteins and patterns of their degradation.

Three key metrics for readout systems in quantum processors are measurement speed, fidelity, and footprint. Fast high-fidelity readout enables midcircuit measurements, a necessary feature for many dynamic algorithms and quantum error correction, while a small footprint facilitates the design of scalable, highly connected architectures with the associated increase in computing performance. Here, we present two complementary demonstrations of fast high-fidelity single-shot readout of spins in silicon quantum dots using a compact, dispersive charge sensor: a radio-frequency single-electron box. The sensor, despite requiring fewer electrodes than conventional detectors, performs at the state of the art achieving spin readout fidelity of 99.2% in less than 6 μs fitted from a physical model. We demonstrate that low-loss high-impedance resonators, highly coupled to the sensing dot, in conjunction with Josephson parametric amplification are instrumental in achieving optimal performance. We quantify the benefit of Pauli spin blockade over spin-dependent tunneling to a reservoir, as the spin-to-charge conversion mechanism in these readout schemes. Our results place dispersive charge sensing at the forefront of readout methodologies for scalable semiconductor spin-based quantum processors.

As in conventional computing, memories for quantum information benefit from high storage density and, crucially, random access, or the ability to read from or write to an arbitrarily chosen register. However, achieving such random access with quantum memories in a dense, hardware-efficient manner remains a challenge. Here we introduce a protocol using chirped pulses to encode qubits within an ensemble of quantum two-level systems, offering both random access and naturally supporting dynamical decoupling to enhance the memory lifetime. We demonstrate the protocol in the microwave regime using donor spins in silicon coupled to a superconducting cavity, storing up to four weak, coherent microwave pulses in distinct memory modes and retrieving them on demand up to 2 ms later. This approach offers the potential for microwave random access quantum memories with lifetimes exceeding seconds, while the chirped pulse phase encoding could also be applied in the optical regime to enhance quantum repeaters and networks.

Abstract Background Non‐melanoma skin cancers (NMSCs) are common and consume many healthcare resources. A health utility is a single preference‐based value for assessing health‐related quality of life, which can be used in economic evaluations. There are scarce data on health utilities for NMSCs. Objectives Using a systematic review approach, we synthesized the current data on NMSC‐related health utilities. Methods A systematic review of studies of NMSC‐related health utilities was conducted in Medline, Embase, and Cochrane databases. Data were extracted based on the protocol and a quality assessment was performed for each study. Results The protocol resulted in 16 studies, involving 121 621 participants. Mean utility values across the studies ranged from 0.56 to 1 for undifferentiated NMSC, 0.84 to 1 for actinic keratosis, 0.45 to 1 for squamous cell carcinoma, and 0.67 to 1 for basal cell carcinoma. There was considerable variability in utilities by type of cancer, stage of diagnosis, time to treatment, treatment modality, and quality of life instrument or method. Utility values were predominantly based on the EuroQol 5‐dimension instrument and ranged from 0.45 to 0.96, while other measurement methods produced values ranging from 0.67 to 1. Lower utility values were observed for advanced cancers and for the time period during and immediately after treatment, after which values gradually returned to pre‐treatment levels. Conclusions Most utility values clustered around relatively high values of 0.8 to 1, suggesting small decrements in quality of life associated with most NMSCs and their precursors. Variability in utilities indicates that careful characterization is required for measures to be used in economic evaluations.

Background: Family-based physical activity promotion presents a promising avenue for promoting whole-family physical activity, but high-quality research is lacking. Objectives: To assess the feasibility, acceptability and preliminary effectiveness of FRESH (Families Reporting Every Step to Health), a child-led online family-based physical activity intervention; and to identify effective and resource-efficient family recruitment strategies. Design: The project consisted of (1) a randomised feasibility trial, (2) a randomised controlled pilot trial and (3) a systematic review and Delphi study. Setting: Norfolk/Suffolk counties, UK. Participants: Families, recruited from schools, workplaces and community settings, were eligible to participate if one child aged 7–11 years and one adult responsible for their care provided written consent; all family members could participate. Interventions: The FRESH intervention, guided by self-determination theory, targeted whole families and was delivered via an online platform. All family members received pedometers and were given website access to select family step challenges to ‘travel’ to target cities around the world, log steps, and track progress as they virtually globetrotted. Families were randomised to FRESH intervention, pedometer-only or control arm. Main outcome measures: Physical (e.g. blood pressure), psychosocial (e.g. family functioning) and behavioural (e.g. device-measured family physical activity) measures were collected at baseline and at 8- and 52-week follow-up. A mixed-methods process evaluation assessed the acceptability of the intervention and evaluation. Data sources review: Systematic search of four databases (Cochrane Library, PubMed, PsycINFO and SCOPUS). Review methods: Articles were screened in duplicate, and data extraction was fully checked. Academic experts participated in the three-round Delphi study. Data were combined to identify effective and resource-efficient family recruitment strategies. Inclusion criteria: Included generally healthy school-aged children and at least one adult; intervention attempted to change physical activity, sedentary behaviour, screen use, diet, or prevent overweight/obesity in multiple family members; presented relevant measure of effect in children and adults. Results: The feasibility study (12 families, 32 participants; 100% retention at 8 weeks) demonstrated the feasibility and acceptability of FRESH, but highlighted that adaptations were required. Of 41 families recruited in the pilot study (149 participants), 98% and 88% were retained at the 8-week and 52-week follow-up, respectively. More children in the FRESH arm self-reported doing more family physical activity, and they thought that FRESH was fun. There were no notable between-group differences in children’s outcomes. Change in moderate to vigorous physical activity at 8 weeks favoured FRESH intervention adults [vs. control: 9.4 minutes/week (95% confidence interval 0.4 to 18.4) vs. pedometer only: 15.3 (95% confidence interval 6.0 to 24.5)], and was stronger in fathers, but this was not maintained. In 49 included studies, apart from recruitment settings and strategies used (reported in 84% and 73% of the studies, respectively), recruitment details were scarce. School-based recruitment was predominant. The Delphi study identified a wide range of recruitment settings and strategies. Limitations: Recruitment was the main limitation of the FRESH studies; generalisability of the proposed recruitment strategies may be limited. Conclusions: This study has demonstrated the feasibility and acceptability of the FRESH intervention. However, we failed to recruit the target sample size and were unable to demonstrate a signal of effectiveness. Future research should employ a multifaceted recruitment approach. Future work: Further refinements to intervention delivery and recruitment methods should be investigated. Study registration: Current Controlled Trials ISRCTN12789422 and PROSPERO CRD42019140042. Funding: This project was funded by the National Institute for Health Research (NIHR) Public Health Research programme and will be published in full in Public Health Research; Vol. 9, No. 9. See the NIHR Journals Library website for further project information.

ABSTRACT: Poultry house dust is composed of fine particles which likely originate from a diverse range of materials such as feed, litter, excreta, and feathers. Little is known about the contribution of these sources to broiler house airborne dust so the present study was designed to identify the relative contributions of these sources. Samples of feed, excreta, feather, and bedding, known mixtures of these and settled dust from 28 broiler chicken flocks were tested for the concentration of 18 chemical elements. A chemometrics approach (the application of multivariate statistical techniques to chemical analysis data) was used to identify the primary source material in broiler chicken house dust samples. Scanning electron microscopy (SEM) was also used to analyze dust sample particulates based on examination of source materials. Excreta was found to be the main component of broiler chicken house dust, both by SEM and chemometric analysis. SEM of experimental flock dust between 7 and 35 days of age (d) revealed that the contribution of excreta to dust increased with age from 60% at 7 d to 95% at 28 d (P < 0.001). The proportion of bedding and feed in dust declined with age while the contribution of feather material remained low throughout. This study demonstrates that excreta provides the bulk of the material in poultry dust samples with bedding material, feed and feather material providing lower proportions. The relative contributions of these materials to dust varies with age of birds at dust collection. Additional research is required to determine the health and diagnostic implications of this variation.

The progress in pre-clinical drug discovery for Wilms tumor (WT) is limited by a lack of disease models. Here, the authors develop 45 heterotopic WT patient-derived xenografts including several anaplastic models that recapitulate the biological heterogeneity of WT, and propose this as a resource for evaluating future therapeutics for WT.

Abstract Background The WBRTMel trial is a multinational, open-label, phase III randomised controlled trial comparing whole brain radiotherapy (WBRT) to observation following local treatment of one to three melanoma brain metastases with surgery and/or stereotactic irradiation. The primary trial endpoint was to determine the effect of adding WBRT to local treatment on distant intracranial control, and the secondary endpoints were neurocognitive function, quality of life (QoL), performance status, overall survival, death from intracranial causes, death from melanoma and cost-effectiveness. Objective The objective of this update is to outline and publish the pre-determined statistical analysis plan (SAP) before the database lock and the start of analysis. Methods The SAP describes basic analysis principles, methods for dealing with a range of commonly encountered data analysis issues and the specific statistical procedures for analysing efficacy and safety outcomes. The SAP was approved after closure of recruitment and before completion of patient follow-up. It outlines the planned primary analyses and a range of subgroup and sensitivity analyses regarding the clinical and QoL outcomes. Health economic outcomes are not included in this plan but will be analysed separately. The SAP will be adhered to for the final data analysis of this trial to avoid analysis bias arising from knowledge of the data. Results The resulting SAP is consistent with best practice and will allow open and transparent reporting. Conclusion We have developed a SAP for the WBRTMel trial which will be followed to ensure high-quality standards of internal validity to minimise analysis bias. Trial registration ANZ Clinical Trials Registry, ACTRN12607000512426. Registered on 9 October 2007. ClinicalTrials.gov, NCT01503827. Registered on 4 January 2012. Trial group reference numbers ANZMTG 01.07, TROG 08.05.

Biomass and yield are important variables used for assessing agricultural production. However, these variables are difficult to estimate for individual plants at the farm scale and may be affected by abiotic stressors such as salinity. In this study, the wild tomato species, Solanum pimpinellifolium, was evaluated through field and UAV-based assessment of 600 control and 600 salt-treated plants. The aim of this research was to determine, if UAV-based imagery, collected one, two, four, six, seven and eight weeks before harvest could predict fresh shoot mass, tomato fruit numbers, and yield mass at harvest and if predictions varied for control and salt-treated plants. A Random Forest approach was used to model biomass and yield. The results showed that shape features such as plant area, border length, width and length had the highest importance in the random forest models. A week prior to harvest, the explained variance of fresh shoot mass, number of fruits and yield mass were 86.60%, 59.46% and 61.09%, respectively. The explained variance was reduced as a function of time to harvest. Separate models may be required for predicting yield of salt-stressed plants, whereas the prediction of yield for control plants was less affected if the model included salt-stressed plants. This research demonstrates that it is possible to predict biomass and yield of tomato plants up to four weeks prior to harvest, and potentially earlier in the absence of severe weather events.

Abstract Background Patient-reported measures are increasingly recognized as important predictors of clinical outcomes in peritoneal dialysis (PD). We sought to understand associations between patient-reported perceptions of the advantages and disadvantages of PD and clinical outcomes. Methods In this cohort study, 2760 PD patients in the Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS) completed a questionnaire on their PD experience, between 2014 and 2017. In this questionnaire, PDOPPS patients rated 17 aspects of their PD experience on a 5-category ordinal scale, with responses scored from − 2 (major disadvantage) to + 2 (major advantage). An advantage/disadvantage score (ADS) was computed for each patient by averaging their response scores. The ADS, along with each of these 17 aspects, were used as exposures. Outcomes included mortality, transition to hemodialysis (HD), patient-reported quality of life (QOL), and depression. Cox regression was used to estimate associations between ADS and mortality, transition to HD, and a composite of the two. Logistic regression with generalized estimating equations was used to estimate cross-sectional associations of ADS with QOL and depression. Results While 7% of PD patients had an ADS